Imaging breast cancer using hyperpolarized carbon-13 MRI.

Our purpose is to investigate the feasibility of imaging tumor metabolism in breast cancer patients using 13C magnetic resonance spectroscopic imaging (MRSI) of hyperpolarized 13C label exchange between injected [1-13C]pyruvate and the endogenous tumor lactate pool. Treatment-naïve breast cancer patients were recruited: four triple-negative grade 3 cancers; two invasive ductal carcinomas that were estrogen and progesterone receptor-positive (ER/PR+) and HER2/neu-negative (HER2-), one grade 2 and one grade 3; and one grade 2 ER/PR+ HER2- invasive lobular carcinoma (ILC). Dynamic 13C MRSI was performed following injection of hyperpolarized [1-13C]pyruvate. Expression of lactate dehydrogenase A (LDHA), which catalyzes 13C label exchange between pyruvate and lactate, hypoxia-inducible factor-1 (HIF1α), and the monocarboxylate transporters MCT1 and MCT4 were quantified using immunohistochemistry and RNA sequencing. We have demonstrated the feasibility and safety of hyperpolarized 13C MRI in early breast cancer. Both intertumoral and intratumoral heterogeneity of the hyperpolarized pyruvate and lactate signals were observed. The lactate-to-pyruvate signal ratio (LAC/PYR) ranged from 0.021 to 0.473 across the tumor subtypes (mean ± SD: 0.145 ± 0.164), and a lactate signal was observed in all of the grade 3 tumors. The LAC/PYR was significantly correlated with tumor volume (R = 0.903, P = 0.005) and MCT 1 (R = 0.85, P = 0.032) and HIF1α expression (R = 0.83, P = 0.043). Imaging of hyperpolarized [1-13C]pyruvate metabolism in breast cancer is feasible and demonstrated significant intertumoral and intratumoral metabolic heterogeneity, where lactate labeling correlated with MCT1 expression and hypoxia.

Observational study using video recordings to explore the first hour after admission to a neonatal intensive care unit.

AIM: To explore the admission process to our neonatal intensive care unit. METHODS: A first phase quality improvement initiative was conducted. We utilised observational video recording of a convenience sample of inborn admissions. Two remote GoPro cameras were placed, one giving an overview of activity and the other focussed on the infant. Recordings captured the first hour after admission including transfer to the neonatal intensive care unit by the birthing team. The video footage of each case study was reviewed by a multidisciplinary panel using an agreed semi-quantitative analysis of events. RESULTS: Ten admissions to the neonatal intensive care unit were video recorded between June and October 2018. Gestational age 282 -401 . A focus on maintaining airway support was inconsistent as was the ability to provide continuous monitoring of vital signs. Overall leadership of the process was lacking and handover often appeared fragmented. Median temperature on admission was 362 (354 -373 ) °C. Vascular access and fluid management occurred at a median of 36 (13-67) minutes. CONCLUSIONS: Planning and approval for this study were protracted, particularly negotiating the use of video recording. Anecdotally, this delay is thought to have contributed to an improvement in managing admissions, particularly when maintaining airway support and monitoring. However, our baseline data have highlighted a lack of leadership, fragmented handover, low admission temperatures and broad time frames to achieve vascular access. A guideline to streamline handover and nursery transition is currently being implemented; a subsequent evaluation cycle is planned.

Delayed versus Immediate Cord Clamping in Preterm Infants.

BACKGROUND: The preferred timing of umbilical-cord clamping in preterm infants is unclear. METHODS: We randomly assigned fetuses from women who were expected to deliver before 30 weeks of gestation to either immediate clamping of the umbilical cord (≤10 seconds after delivery) or delayed clamping (≥60 seconds after delivery). The primary composite outcome was death or major morbidity (defined as severe brain injury on postnatal ultrasonography, severe retinopathy of prematurity, necrotizing enterocolitis, or late-onset sepsis) by 36 weeks of postmenstrual age. Analyses were performed on an intention-to-treat basis, accounting for multiple births. RESULTS: Of 1634 fetuses that underwent randomization, 1566 were born alive before 30 weeks of gestation; of these, 782 were assigned to immediate cord clamping and 784 to delayed cord clamping. The median time between delivery and cord clamping was 5 seconds and 60 seconds in the respective groups. Complete data on the primary outcome were available for 1497 infants (95.6%). There was no significant difference in the incidence of the primary outcome between infants assigned to delayed clamping (37.0%) and those assigned to immediate clamping (37.2%) (relative risk, 1.00; 95% confidence interval, 0.88 to 1.13; P=0.96). The mortality was 6.4% in the delayed-clamping group and 9.0% in the immediate-clamping group (P=0.03 in unadjusted analyses; P=0.39 after post hoc adjustment for multiple secondary outcomes). There were no significant differences between the two groups in the incidences of chronic lung disease or other major morbidities. CONCLUSIONS: Among preterm infants, delayed cord clamping did not result in a lower incidence of the combined outcome of death or major morbidity at 36 weeks of gestation than immediate cord clamping. (Funded by the Australian National Health and Medical Research Council [NHMRC] and the NHMRC Clinical Trials Centre; APTS Australian and New Zealand Clinical Trials Registry number, ACTRN12610000633088 .).

The interaction of Escherichia coli O157 :H7 and Salmonella Typhimurium flagella with host cell membranes and cytoskeletal components.

Bacterial flagella have many established roles beyond swimming motility. Despite clear evidence of flagella-dependent adherence, the specificity of the ligands and mechanisms of binding are still debated. In this study, the molecular basis of Escherichia coli O157:H7 and Salmonella enterica serovar Typhimurium flagella binding to epithelial cell cultures was investigated. Flagella interactions with host cell surfaces were intimate and crossed cellular boundaries as demarcated by actin and membrane labelling. Scanning electron microscopy revealed flagella disappearing into cellular surfaces and transmission electron microscopy of S. Typhiumurium indicated host membrane deformation and disruption in proximity to flagella. Motor mutants of E. coli O157:H7 and S. Typhimurium caused reduced haemolysis compared to wild-type, indicating that membrane disruption was in part due to flagella rotation. Flagella from E. coli O157 (H7), EPEC O127 (H6) and S. Typhimurium (P1 and P2 flagella) were shown to bind to purified intracellular components of the actin cytoskeleton and directly increase in vitro actin polymerization rates. We propose that flagella interactions with host cell membranes and cytoskeletal components may help prime intimate attachment and invasion for E. coli O157:H7 and S. Typhimurium, respectively.

An eQTL in the cystathionine beta synthase gene is linked to osteoporosis in laying hens.

BACKGROUND: Skeletal damage is a challenge for laying hens because the physiological adaptations required for egg laying make them susceptible to osteoporosis. Previously, we showed that genetic factors explain 40% of the variation in end of lay bone quality and we detected a quantitative trait locus (QTL) of large effect on chicken chromosome 1. The aim of this study was to combine data from the commercial founder White Leghorn population and the F2 mapping population to fine-map this QTL and understand its function in terms of gene expression and physiology. RESULTS: Several single nucleotide polymorphisms on chromosome 1 between 104 and 110 Mb (galGal6) had highly significant associations with tibial breaking strength. The alternative genotypes of markers of large effect that flanked the region had tibial breaking strengths of 200.4 vs. 218.1 Newton (P < 0.002) and, in a subsequent founder generation, the higher breaking strength genotype was again associated with higher breaking strength. In a subsequent generation, cortical bone density and volume were increased in individuals with the better bone genotype but with significantly reduced medullary bone quality. The effects on cortical bone density were confirmed in a further generation and was accompanied by increased mineral maturity of the cortical bone as measured by infrared spectrometry and there was evidence of better collagen cross-linking in the cortical bone. Comparing the transcriptome of the tibia from individuals with good or poor bone quality genotypes indicated four differentially-expressed genes at the locus, one gene, cystathionine beta synthase (CBS), having a nine-fold higher expression in the genotype for low bone quality. The mechanism was cis-acting and although there was an amino-acid difference in the CBS protein between the genotypes, there was no difference in the activity of the enzyme. Plasma homocysteine concentration, the substrate of CBS, was higher in the poor bone quality genotype. CONCLUSIONS: Validated markers that predict bone strength have been defined for selective breeding and a gene was identified that may suggest alternative ways to improve bone health in addition to genetic selection. The identification of how genetic variants affect different aspects of bone turnover shows potential for translational medicine.

Program Development of Integrated Psychological Services for Hospitalized Patients with Intravenous Drug Use Histories.

Amid rising trends in opioid use, hospitalizations for health conditions secondary to intravenous drug use are becoming more common. Such patients often require prolonged hospitalizations and frequently present with substance use histories, co-occurring mental health diagnoses, and unique behavioral health needs. These issues can adversely impact completion of medical treatment and place added burden on hospital staff. There is a growing need for medical institutions to develop policies and procedures which address the specific emotional, behavioral, and substance use needs of this patient population. Because guidelines for doing so are sparse in the literature, this study outlines the University of Vermont Medical Center's process of developing an in-hospital care agreement intended to (1) increase patient access to in-hospital need assessments, psychotherapy, and medication for opioid use disorders, (2) increase referrals for opioid use treatment beyond hospitalization, (3) standardize staff response to common challenging behaviors, and (4) provide staff with education and support for interacting with patients in effective ways. The multidisciplinary process of developing this care agreement, its specific details, lessons learned, and anticipated future directions are also discussed.

Quantifying normal human brain metabolism using hyperpolarized [1-13C]pyruvate and magnetic resonance imaging.

Hyperpolarized 13C Magnetic Resonance Imaging (13C-MRI) provides a highly sensitive tool to probe tissue metabolism in vivo and has recently been translated into clinical studies. We report the cerebral metabolism of intravenously injected hyperpolarized [1-13C]pyruvate in the brain of healthy human volunteers for the first time. Dynamic acquisition of 13C images demonstrated 13C-labeling of both lactate and bicarbonate, catalyzed by cytosolic lactate dehydrogenase and mitochondrial pyruvate dehydrogenase respectively. This demonstrates that both enzymes can be probed in vivo in the presence of an intact blood-brain barrier: the measured apparent exchange rate constant (kPL) for exchange of the hyperpolarized 13C label between [1-13C]pyruvate and the endogenous lactate pool was 0.012 ±â€¯0.006 s-1 and the apparent rate constant (kPB) for the irreversible flux of [1-13C]pyruvate to [13C]bicarbonate was 0.002 ±â€¯0.002 s-1. Imaging also revealed that [1-13C]pyruvate, [1-13C]lactate and [13C]bicarbonate were significantly higher in gray matter compared to white matter. Imaging normal brain metabolism with hyperpolarized [1-13C]pyruvate and subsequent quantification, have important implications for interpreting pathological cerebral metabolism in future studies.

Associations of measures of systemic blood flow used in a randomized trial of delayed cord clamping in preterm infants.

OBJECTIVE: To determine associations of low superior vena cava (SVC) flow (≤55 ml/kg/min) and low right ventricular output (RVO) (≤150 ml/kg/min) in preterm infants. DESIGN/METHODS: An observational study in infants <30 weeks gestation randomized to receive immediate (<10 s) or delayed cord clamping (DCC) (≥60 s). RESULTS: The study enrolled 265 infants with a mean (SD) gestation 28 (2) weeks. Eighty-six (33%) infants had low SVC flow and 81 (31%) infants had low RVO. In multivariate analysis, low SVC flow was associated with gestation; low RVO was associated with DCC, gender and 5-minute Apgar; whereas mean RVO was negatively associated with both FiO2 and mean airway pressure (MAP) at 9 h and 24 h. Low SVC flow was associated with ductus arteriosus (DA) treatment. Infants with low RVO had higher mortality on univariate analysis, but this was not significant after adjusting for gestation. CONCLUSIONS: SVC flow was associated with gestation, whilst RVO was associated with placental transfusion, gender, condition at birth, and early respiratory adaptation. Compared to infants with normal values, more infants with low SVC flow were treated for DA, but infants with low RVO had no significant difference in mortality or morbidity.

Correction: Associations of measures of systemic blood flow used in a randomized trial of delayed cord clamping in preterm infants.

A correction to this paper has been published and can be accessed via a link at the top of the paper.

Discovery of potent azaindazole leucine-rich repeat kinase 2 (LRRK2) inhibitors possessing a key intramolecular hydrogen bond - Part 2.

The discovery of disease-modifying therapies for Parkinson's Disease (PD) represents a critical need in neurodegenerative medicine. Genetic mutations in LRRK2 are risk factors for the development of PD, and some of these mutations have been linked to increased LRRK2 kinase activity and neuronal toxicity in cellular and animal models. As such, research towards brain-permeable kinase inhibitors of LRRK2 has received much attention. In the course of a program to identify structurally diverse inhibitors of LRRK2 kinase activity, a 5-azaindazole series was optimized for potency, metabolic stability and brain penetration. A key design element involved the incorporation of an intramolecular hydrogen bond to increase permeability and potency against LRRK2. This communication will outline the structure-activity relationships of this matched pair series including the challenge of obtaining a desirable balance between metabolic stability and brain penetration.

Electroreception in marine fishes: chondrichthyans.

Electroreception in marine fishes occurs across a variety of taxa and is best understood in the chondrichthyans (sharks, skates, rays, and chimaeras). Here, we present an up-to-date review of what is known about the biology of passive electroreception and we consider how electroreceptive fishes might respond to electric and magnetic stimuli in a changing marine environment. We briefly describe the history and discovery of electroreception in marine Chondrichthyes, the current understanding of the passive mode, the morphological adaptations of receptors across phylogeny and habitat, the physiological function of the peripheral and central nervous system components, and the behaviours mediated by electroreception. Additionally, whole genome sequencing, genetic screening and molecular studies promise to yield new insights into the evolution, distribution, and function of electroreceptors across different environments. This review complements that of electroreception in freshwater fishes in this special issue, which provides a comprehensive state of knowledge regarding the evolution of electroreception. We conclude that despite our improved understanding of passive electroreception, several outstanding gaps remain which limits our full comprehension of this sensory modality. Of particular concern is how electroreceptive fishes will respond and adapt to a marine environment that is being increasingly altered by anthropogenic electric and magnetic fields.

A chicken bioreactor for efficient production of functional cytokines.

BACKGROUND: The global market for protein drugs has the highest compound annual growth rate of any pharmaceutical class but their availability, especially outside of the US market, is compromised by the high cost of manufacture and validation compared to traditional chemical drugs. Improvements in transgenic technologies allow valuable proteins to be produced by genetically-modified animals; several therapeutic proteins from such animal bioreactors are already on the market after successful clinical trials and regulatory approval. Chickens have lagged behind mammals in bioreactor development, despite a number of potential advantages, due to the historic difficulty in producing transgenic birds, but the production of therapeutic proteins in egg white of transgenic chickens would substantially lower costs across the entire production cycle compared to traditional cell culture-based production systems. This could lead to more affordable treatments and wider markets, including in developing countries and for animal health applications. RESULTS: Here we report the efficient generation of new transgenic chicken lines to optimize protein production in eggs. As proof-of-concept, we describe the expression, purification and functional characterization of three pharmaceutical proteins, the human cytokine interferon α2a and two species-specific Fc fusions of the cytokine CSF1. CONCLUSION: Our work optimizes and validates a transgenic chicken system for the cost-effective production of pure, high quality, biologically active protein for therapeutics and other applications.

The Effect of Antenatal Betamethasone on White Matter Inflammation and Injury in Fetal Sheep and Ventilated Preterm Lambs.

Antenatal administration of betamethasone (BM) is a common antecedent of preterm birth, but there is limited information about its impact on the acute evolution of preterm neonatal brain injury. We aimed to compare the effects of maternal BM in combination with mechanical ventilation on the white matter (WM) of late preterm sheep. At 0.85 of gestation, pregnant ewes were randomly assigned to receive intra-muscular (i.m.) saline (n = 9) or i.m. BM (n = 13). Lambs were delivered and unventilated controls (UVCSal, n = 4; UVCBM, n = 6) were humanely killed without intervention; ventilated lambs (VentSal, n = 5; VentBM, n = 7) were injuriously ventilated for 15 min, followed by conventional ventilation for 75 min. Cardiovascular and cerebral haemodynamics and oxygenation were measured continuously. The cerebral WM underwent assessment of inflammation and injury, and oxidative stress was measured in the cerebrospinal fluid (CSF). In the periventricular and subcortical WM tracts, the proportion of amoeboid (activated) microglia, the density of astrocytes, and the number of blood vessels with protein extravasation were higher in UVCBM than in UVCSal (p < 0.05 for all). During ventilation, tidal volume, mean arterial pressure, carotid blood flow, and oxygen delivery were higher in -VentBM lambs (p < 0.05 vs. VentSal). In the subcortical WM, microglial infiltration was increased in the VentSal group compared to UVCSal. The proportion of activated microglia and protein extravasation was higher in the VentBM group compared to VentSal within the periventricular and subcortical WM tracts (p < 0.05). CSF oxidative stress was increased in the VentBM group compared to UVCSal, UVCBM, and VentSal groups (p < 0.05). Antenatal BM was associated with inflammation and vascular permeability in the WM of late preterm fetal sheep. During the immediate neonatal period, the increased carotid perfusion and oxygen delivery in BM-treated lambs was associated with increased oxidative stress, microglial activation and microvascular injury.

A recurrent de novo mutation in ACTG1 causes isolated ocular coloboma.

Ocular coloboma (OC) is a defect in optic fissure closure and is a common cause of severe congenital visual impairment. Bilateral OC is primarily genetically determined and shows marked locus heterogeneity. Whole-exome sequencing (WES) was used to analyze 12 trios (child affected with OC and both unaffected parents). This identified de novo mutations in 10 different genes in eight probands. Three of these genes encoded proteins associated with actin cytoskeleton dynamics: ACTG1, TWF1, and LCP1. Proband-only WES identified a second unrelated individual with isolated OC carrying the same ACTG1 allele, encoding p.(Pro70Leu). Both individuals have normal neurodevelopment with no extra-ocular signs of Baraitser-Winter syndrome. We found this mutant protein to be incapable of incorporation into F-actin. The LCP1 and TWF1 variants each resulted in only minor disturbance of actin interactions, and no further plausibly causative variants were identified in these genes on resequencing 380 unrelated individuals with OC.

Microbiota in Exhaled Breath Condensate and the Lung.

The lung microbiota is commonly sampled using relatively invasive bronchoscopic procedures. Exhaled breath condensate (EBC) collection potentially offers a less invasive alternative for lung microbiota sampling. We compared lung microbiota samples retrieved by protected specimen brushings (PSB) and exhaled breath condensate collection. We also sought to assess whether aerosolized antibiotic treatment would influence the lung microbiota and whether this change could be detected in EBC. EBC was collected from 6 conscious sheep and then from the same anesthetized sheep during mechanical ventilation. Following the latter EBC collection, PSB samples were collected from separate sites within each sheep lung. On the subsequent day, each sheep was then treated with nebulized colistimethate sodium. Two days after nebulization, EBC and PSB samples were again collected. Bacterial DNA was quantified using 16S rRNA gene quantitative PCR. The V2-V3 region of the 16S rRNA gene was amplified by PCR and sequenced using Illumina MiSeq. Quality control and operational taxonomic unit (OTU) clustering were performed with mothur. The EBC samples contained significantly less bacterial DNA than the PSB samples. The EBC samples from anesthetized animals clustered separately by their bacterial community compositions in comparison to the PSB samples, and 37 bacterial OTUs were identified as differentially abundant between the two sample types. Despite only low concentrations of colistin being detected in bronchoalveolar lavage fluid, PSB samples were found to differ by their bacterial compositions before and after colistimethate sodium treatment. Our findings indicate that microbiota in EBC samples and PSB samples are not equivalent.IMPORTANCE Sampling of the lung microbiota usually necessitates performing bronchoscopic procedures that involve a hospital visit for human participants and the use of trained staff. The inconvenience and perceived discomfort of participating in this kind of research may deter healthy volunteers and may not be a safe option for patients with advanced lung disease. This study set out to evaluate a less invasive method for collecting lung microbiota samples by comparing samples taken via protected specimen brushings (PSB) to those taken via exhaled breath condensate (EBC) collection. We found that there was less bacterial DNA in EBC samples compared with that in PSB samples and that there were differences between the bacterial communities in the two sample types. We conclude that while EBC and PSB samples do not produce equivalent microbiota samples, the study of the EBC microbiota may still be of interest.

The longitudinal effect of ejaculation on seminal vesicle fluid volume and whole-prostate ADC as measured on prostate MRI.

OBJECTIVE: To prospectively investigate the longitudinal effect of ejaculatory abstinence on MRI-measured seminal vesicle (SV) volume and whole-prostate ADC over consecutive days. METHODS: 15 healthy male volunteers (mean 35.9 years, range 27-53) underwent 3-T MRI at baseline and 1, 2 and 3 days post-ejaculation. Prostate and SV volumes were derived by volume segmentation and whole-gland apparent diffusion coefficient (ADC) values calculated. A mixed-effects linear regression compared ADC values and prostate/seminal vesicle volumes in each volunteer between studies in a pairwise manner. RESULTS: All subjects completed the four MRIs. Mean prostate volume was 22.45 cm3 (range 13.04-31.21 cm3), with no change between the four studies (p = 0.89-0.99). 13/15 subjects showed SV volume reduction from baseline to day 1, with group-mean decreasing from 6.45 to 4.80 cm3 (-25.6%, p < 0.001), and a significant reduction from baseline to day 2 (-18.1%, p = 0.002). There was a significant volume increase from both day 1 (+21.3%, p = 0.006) and day 2 (+10.2%, p = 0.022) to day 3 post-ejaculation. There was a significant reduction in ADC from 1.105 at baseline to 1.056 × 10-3 mm2/s at day 1 (mean -4.3%, p = 0.009). CONCLUSION: The longitudinal effect of ejaculation on SV volume was demonstrated. Significant reductions in SV volume and whole-gland ADC were observed post-ejaculation, supporting a 3-day period of abstinence before prostate MRI. KEY POINTS: • Seminal vesicle volume significantly reduced 24 h post-ejaculation remaining reduced at day 2 • Seminal vesicle fluid volume significantly increased from day 1 to day 3 post-ejaculation • There was a significant reduction in whole-gland prostate ADC values day 1 post-ejaculation • 3-day abstinence from ejaculation is required to ensure maximal seminal vesicle distension.

Assessment of early treatment response to neoadjuvant chemotherapy in breast cancer using non-mono-exponential diffusion models: a feasibility study comparing the baseline and mid-treatment MRI examinations.

OBJECTIVES: To assess the feasibility of the mono-exponential, bi-exponential and stretched-exponential models in evaluating response of breast tumours to neoadjuvant chemotherapy (NACT) at 3 T. METHODS: Thirty-six female patients (median age 53, range 32-75 years) with invasive breast cancer undergoing NACT were enrolled for diffusion-weighted MRI (DW-MRI) prior to the start of treatment. For assessment of early response, changes in parameters were evaluated on mid-treatment MRI in 22 patients. DW-MRI was performed using eight b values (0, 30, 60, 90, 120, 300, 600, 900 s/mm2). Apparent diffusion coefficient (ADC), tissue diffusion coefficient (D t), vascular fraction (ƒ), distributed diffusion coefficient (DDC) and alpha (α) parameters were derived. Then t tests compared the baseline and changes in parameters between response groups. Repeatability was assessed at inter- and intraobserver levels. RESULTS: All patients underwent baseline MRI whereas 22 lesions were available at mid-treatment. At pretreatment, mean diffusion coefficients demonstrated significant differences between groups (p < 0.05). At mid-treatment, percentage increase in ADC and DDC showed significant differences between responders (49 % and 43 %) and non-responders (21 % and 32 %) (p = 0.03, p = 0.04). Overall, stretched-exponential parameters showed excellent repeatability. CONCLUSION: DW-MRI is sensitive to baseline and early treatment changes in breast cancer using non-mono-exponential models, and the stretched-exponential model can potentially monitor such changes. KEY POINTS: • Baseline diffusion coefficients demonstrated significant differences between complete pathological responders and non-responders. • Increase in ADC and DDC at mid-treatment can discriminate responders and non-responders. • The ƒ fraction at mid-treatment decreased in responders whereas increased in non-responders. • The mono- and stretched-exponential models showed excellent inter- and intrarater repeatability. • Treatment effects can potentially be assessed by non-mono-exponential diffusion models.

Ventilation-induced lung injury is not exacerbated by growth restriction in preterm lambs.

Intrauterine growth restriction (IUGR) and preterm birth are frequent comorbidities and, combined, increase the risk of adverse respiratory outcomes compared with that in appropriately grown (AG) infants. Potential underlying reasons for this increased respiratory morbidity in IUGR infants compared with AG infants include altered fetal lung development, fetal lung inflammation, increased respiratory requirements, and/or increased ventilation-induced lung injury. IUGR was surgically induced in preterm fetal sheep (0.7 gestation) by ligation of a single umbilical artery. Four weeks later, preterm lambs were euthanized at delivery or delivered and ventilated for 2 h before euthanasia. Ventilator requirements, lung inflammation, early markers of lung injury, and morphological changes in lung parenchymal and vascular structure and surfactant composition were analyzed. IUGR preterm lambs weighed 30% less than AG preterm lambs, with increased brain-to-body weight ratio, indicating brain sparing. IUGR did not induce lung inflammation or injury or alter lung parenchymal and vascular structure compared with AG fetuses. IUGR and AG lambs had similar oxygenation and respiratory requirements after birth and had significant, but similar, increases in proinflammatory cytokine expression, lung injury markers, gene expression, and surfactant phosphatidylcholine species compared with unventilated controls. IUGR does not induce pulmonary structural changes in our model. Furthermore, IUGR and AG preterm lambs have similar ventilator requirements in the immediate postnatal period. This study suggests that increased morbidity and mortality in IUGR infants is not due to altered lung tissue or vascular structure, or to an altered response to early ventilation.

Effect of Delayed Cord Clamping on Systemic Blood Flow: A Randomized Controlled Trial.

OBJECTIVE: To determine whether delayed cord clamping improves systemic blood flow compared with immediate cord clamping in very preterm infants in the first 24 hours. STUDY DESIGN: Women delivering at <30 weeks' gestation at 5 tertiary centers were randomized to receive immediate cord clamping (<10 seconds) or delayed cord clamping (≥60 seconds). Echocardiography and cardiorespiratory data were collected at 3, 9, and 24 hours after birth. The primary outcome was mean lowest superior vena cava (SVC) flow. RESULTS: Of 266 infants enrolled, 133 were randomized to immediate cord clamping and 133 to delayed cord clamping. The 2 groups were similar at baseline, including mean gestation (immediate cord clamping 28 weeks vs delayed cord clamping 28 weeks) and birth weight (immediate cord clamping 1003 g vs delayed cord clamping 1044 g). There was no significant difference between groups in the primary outcome of mean lowest SVC flow (immediate cord clamping 71.4 mL/kg/min [SD 28.1] vs delayed cord clamping 70.2 mL/kg/min [SD 26.9]; P = .7). For secondary outcomes, hemoglobin increased by 0.9 g/dL at 6 hours in the group with delayed cord clamping (95% CI 3.9, 14.4; P = .0005, adjusted for baseline). The group with delayed cord clamping had lower right ventricular output (-21.9 mL/kg/min, 95% CI -39.0, -4.7; P = .01). Rates of treated hypotension, ductus arteriosus size and shunt direction, and treatment of the ductus arteriosus were similar. CONCLUSIONS: Delayed cord clamping had no effect on systemic blood flow measured as mean lowest SVC flow in the first 24 hours in infants <30 weeks' gestation. TRIAL REGISTRATION: Australia New Zealand Clinical Trials Registry: ACTRN12610000633088.

A comparison of quantitative methods for clinical imaging with hyperpolarized (13)C-pyruvate.

Dissolution dynamic nuclear polarization (DNP) enables the metabolism of hyperpolarized (13)C-labelled molecules, such as the conversion of [1-(13)C]pyruvate to [1-(13)C]lactate, to be dynamically and non-invasively imaged in tissue. Imaging of this exchange reaction in animal models has been shown to detect early treatment response and correlate with tumour grade. The first human DNP study has recently been completed, and, for widespread clinical translation, simple and reliable methods are necessary to accurately probe the reaction in patients. However, there is currently no consensus on the most appropriate method to quantify this exchange reaction. In this study, an in vitro system was used to compare several kinetic models, as well as simple model-free methods. Experiments were performed using a clinical hyperpolarizer, a human 3 T MR system, and spectroscopic imaging sequences. The quantitative methods were compared in vivo by using subcutaneous breast tumours in rats to examine the effect of pyruvate inflow. The two-way kinetic model was the most accurate method for characterizing the exchange reaction in vitro, and the incorporation of a Heaviside step inflow profile was best able to describe the in vivo data. The lactate time-to-peak and the lactate-to-pyruvate area under the curve ratio were simple model-free approaches that accurately represented the full reaction, with the time-to-peak method performing indistinguishably from the best kinetic model. Finally, extracting data from a single pixel was a robust and reliable surrogate of the whole region of interest. This work has identified appropriate quantitative methods for future work in the analysis of human hyperpolarized (13)C data.